Preparation of diazabicyclo-octane



E. C. HERRICK PREPARATION OF DIAZABICYCLO-OCTANE Filed Dec. 17, 1956 May 17, 1960 United States Patent() PREPARATION F DIAZABICYCLO-OCTANE n Elbert C. Herrick, Media, Pa., assignor to Houdry Process Corporation, Wilmington, Del., a corporation of Delaware Application December 17, 1956, Serial No. 628,723

12 Claims. (Cl. 260-268) The present invention relates tothe preparation of 1,4-diazabicyclo-(2.2.2)-octane, also known as triethylene diamine, in comparatively high yields and to the improved recovery of the same from reaction mixtures as a product of acceptable purity. y

Diazabicyclo-octane is best known in the literature as a reaction product of N-Z-bromoethyl piperazine hydrobromide. Because of the insuicient availability of this starting material, this route does not provide an attractive commercial source for preparation of diazabicyclo-octane. While the preparation of bicyclo diamines of this type has been long sought by organic chemists and many dilferent methods are suggested inthe literature for preparation of such compounds, some of which utilize alkyl, alkylol, or other substituted aliphatic amines as starting materials, the product was obtainedin only poor yields in the order of up to about 2% of theory, or on a product presumed to be diazabicyclo-octane, later identication showed the recovered product to be other than the bicyclo diamine sought.

Later work on the attempted preparation of diazabicyclo-octane includes that of Hromatka (Berichte der Deutschen Chemischen Ges. 1942), who investigated the eiiect of temperature in, heating diethanolamine hydrochloride in the 20G-260 C. range. The best results by Hromatka reported 2% diazabicyclo-octane obtained by 18 hour-s heating of the diethanolamine hydrochloride at 220 C. At the higher temperatures tried, sudden dissociation was noted and failure to recover diazabicyclooctane from the reaction products. Other syntheses carried out by Hromatka, e.g. in attempting to prepare diazabicyclo-octane by heating triethanolamine with ammonium chloride and by reactionY of ethanolamine hydrochloride with diethanolamine, produced no better yields. Isolation of minute amounts o f diazabicyclooctane from the reaction mixture was effected by separation of its perchlorate from the more soluble perchlorate of the accompanying morpholine.

More recent work (Ishiguro et al., Journal Pharmaceutical Society, Japan, 1955), reports successful preparation of diazabicyclo-octane from N-haloalkyl derivatives of piperazine hydrohalides over silica-alumina.

The presence of small amounts of diazabicyclo-octane has also been reported in reaction products obtained in the synthesis of piperazine from various alkyl and alkylol amines.

Among the objects of the present invention are the production of diazabicyclo-octane from, readily available' ferred to as triethylene diamine, has been confirmed as being 1,4-diazabicyclo-(2.2.2)-octane, having the formula:

"ice

I vThe purified base, recovered from the p-nitrophenolate is hygroscopic, melts at 15S-160 C., and is shown to have a molecular weight of 112 by the Rast camphor method. The presence of 2 basic nitrogen atoms is accounted for by titration. It is a weaker base than piperazine, being weakly basic to phenolphthalein and basic to methyl red. The perchlorater salt of the base is appreciably soluble in cold water and dissociate explosively without melting at 300 C.

Because of the unavailability of diazabicyclo-octane in suiiicient quantities, many of its possible commercial usesV evidenced by its physical and chemical propertiesl have not been fully investigated. The base readily forms the dipicrate salt which is a sensitive explosive. Being a relatively strong nitrogen base, it forms quaternary N- salts having cationic activity useful as detergents, dispersants, and other surface active agents. The base and its lacid salts, including the tartarate, phosphate, and acetate, should be useful, as are the corresponding piperaz-ine salts, as effective vermifuges for poultry and swine, beingused as such in direct medication or as a component (0.1 to 3%), of animal feeds.

In accordance with the invention, diazabicyclo-(2.2.2) octane is prepared by the vapor phase reaction of an aliphatic amine, such as an alkylene polyamine or alkanol amine, over acidic solid catalyst in a temperature range of 300 to 500 v, C. obtaining this compound with accompanying production of piperazine. The reaction product is fractionated by distillation and diazabicyclooctane is recovered in a fraction boiling above piperazine and is purified by several methods, e.g. by treatment of such fraction with low boiling liquid hydrocarbon.

The preferred method o-f operation is illustrated in the accompanying flow diagram. Pumps, heat exchangers, scrubbers, storage vessels, and other conventional auxiliary equipment have been omitted in most instances for sake of clarity. As shown, the starting aliphatic amine is initially vaporized and heated to reaction temperature in a salt bath or other temperature-controlled heater at 10 and passed in vapor form into a iixed bed catalytic reactor at I11. Hydrogen-or -inert gas, such as nitrogen,

`may be introduced at 14 for initial pressurizing (if deaction.

In the illustrative example, hereinafter described in detail, diethylene triamine was employed as the starting material. Other alkyl or alkylol amines can be used instead, and under substantially the same operating conditions, including ethylene diamine, triethylene tetramine, isopropanol-amine, 1,2-diamino propan, N-2-hydroxyethyl ethylene diamine (beta aminoethyl-ethanolamine), and in general those alkylene polyamines and their hydroxyalkyl derivatives corresponding to the formula:

y y HaN-L/--A A is NH2, OH, or an v NH-tiJ-m-OH v (NH-(IJ- -)=-NH group .l .l .l-being an integer from 1 to 4, and y is hydrogen or The preferred catalyst is silica-alumina, particularly of the type familiarly used in catalytic cracking of hydrocarbons, in the form of granules, molded pellets, or beads. Such catalysts include the synthetic dried gel type catalyst formed by suitable impregnation of silica gel, or by co-precipitation of alkali metal silicate with an aluminum compound, to provide a gel comprising V60+90% by weight n SiOg to 40-10% by weight Alzoaandwhich may include `therein other refractory metal oxides such as magnesia or zirconia. Other known silica-alumina catalysts that may be employed include acid-activated Vclays of the montmorillonite and kaolin types. Catalysts contalning a minor quantity of a dehydrogenating metal component,

such as 0.5 to 3% nickel, supported on the silica-alumina carrier, may also be used. Y

The desired diazabicyclo-octaneV product, as well as piperazine, is formed over a reaction temperature range of from about 300 to 500 C., higher temperatures in the range, as from about 330 C. favoring higher over-al1 yields of diazabicyclo-octane and higher proportionate yieldsof diazabicyclo-octane to piperazine. Thus, as reaction temperature is increased over the range from 330 C. to about 360 C. `almost a threefold increase in diazabicyclo-octane yield is obtained. At temperatures above about 430 C. at the practical throughput rates used, additional side reaction products are formed with increasing diiculties Yof separation. AAccordingly, the preferred temperature range at space rates of 0.5 to 2.0 volumes of alkyl amine per hour per volume of catalyst is at about 330-430 C.

The use of elevated pressure is not essential to the operation. In general, pressures from atmospheric to 100 pounds per square inch may be used.- In some instances, particularly when operating at super-atmospheric pressure, it may be desirable `to reduce the partial pressure of the amines in the reaction zone, which may be accomplished by the addition of gaseous diluent, such as hydrogen or inert gas, in quantities of up to mols per mol of amine charged. When the catalyst employed is one containing a hydrogenating metal component, the addition of at least several mols of hydrogen to the reaction zone is particularly recommended.

Referring again to the ow sheet, the vapor efuent from reactor 11 is cooled andlreduced to atmospheric pressure as shown at 15 to separate ammonia formed in the process and other gases from liquid products and unconverted amines, the ammonia being absorbed in water and separated from the other gases. The remaining liquid condensate is sent to a batch stillas shown at 16 for separation into desired fractions. Continuous distillation apparatus, it will be understood, may be employed at this point and elsewhere in the systeminstead of the batch stills described. For batch operation the condensate from 15 is collected as indicated at 17 to provide sucient charge for distillation.V Thevarious fractions, specically shown as separated in the accompanying flow diagram, are based on an operation utilizing diethylene triamine as the freshcharge. It will be understood that with other starting alkylene -or alkylol amines the handling of the various cuts and the cut points will be appropriately modied. In any event, initial distillation at 16 is operated to provide at least, (l) a fraction boiling below piperazine which will include pyrazine and its simple homologues as well as ethylene diamine and other possible alkyl amines within this boiling range from dissociation of diethylene triarnine, (2) a fraction boiling in the approximate range of piperazine and which may include some simple homo logues of piperazine formed in the process, such as methyl piperazine, and (3) a fraction boiling above piperazine which will include diazabicyclo-octane as well as diethylene triamine and other aliphatic amines falling in this boiling range. Y

Assuming that diethylene triamine is employed as the fresh feed, distillation is elected to collect an initial fraction 'indicated at 18 to a' cut point of 125 or up to' 130 C., operating the still at a reflux ratio ofv 10/,1

to about 15/1. The distillate collected at 18 may be sent at least in part to recycle supply as shown at 19, with previous recovery of pyrazine therefrom if desired, as optionally indicated in dotted lines at 20.

The piperazine-containing fraction is then collected as indicated at 22 which may be a cut boiling up to 150 or C., from which piperazine can be separated and recovered in any desired manner. While not presently advocated in view of the existing demand for piperazine on the commercial market, all or part of the piperazine fraction may be treated, if desired, to convert the same to diazabicyclo-octane; for instance by recycling the same to the principal reaction at 11.

When the piperazine fraction of the desired boiling range has been collected, the still bottoms will be collected as shown at 23, for further treatment. It should be noted that diazabicyclo-octane is highly volatile so that a small part thereof will distill below the expected boiling point and will be found in the distillates, from which a portion of the diazabicyclo-octane may be 1'ecovered,if desired, in the separation of other accompanying products.

The collected still bottoms from 23, depending upon the temperature of the nal distillate cut, will be a fraction kboiling above 150 or above 160 C. The bottoms fraction is stripped as indicated at 25 to separate out any lower boiling material remaining therein. For instance, an overhead fraction of up to 150 C. may be initially boiled off as indicated at 26 and returned to still 16 for recovery of any piperazine or other desired products that may be present. The fraction boiling above 150 C. and up to about 190 C., obtained as a heart cut at 27 contains the major portion of the diazabicyclooctane. The bottoms fraction boiling above 190 C. which will contain chieily unreacted diethylene triamine and other aliphatic amines, is returned to recycle supply at 19. If desired, `the recycle material may be purified to remove tars and high boiling polymers as optionally indicated at- 28, to avoid contamination of the catalyst thereby. Y Y

The l50-l90 C. fraction is then further distilled as indicated at 29 to obtain a narrower cut containing the desired diazabicyclo-octane fraction. Accordingly, there is collected a fraction boiling, say, in the range of 168 to C. as Vshown at 30, lower boiling materials being first driven off at 31 and returned to the rst still 16, separately or together with the fraction from still 25,V and the bottoms boiling above 175 C. being withdrawn at 32 and sent'to recyclesupply 19, in whole or part,

` this fraction containing `the major portion of the diethylene thiamine and any otheraliphatic or cyclic amines boiling vin this range, suitable as charge material for further Vwell as in operations wherein approximately equal parts of fresh and recycle products were charged and those in which'the charge contained no fresh diethylene triamine or other alkylene amine.

`The cooled Vdiazabir..yclooctane fraction at 33 comprises a mixture of crystalline and liquid products. It is purified, as indicated, byetrituration one or more times with at least an equal volume of n-pentane land preferably by 2 or 3 successive treatments with'fresh n-pentane. Cooling and filtration yields (34) a white crystalline solid of fairly pure diazabicyclo-octane (95|%). The light solvent plus pentane soluble component 35 is distilled to recover n-pentane'solvent.- The remaining mushy liquid and crystalline product (36) are separated by ltration, giving a dark colored oily residue 37 containing about 26% diazabicyclo-octane and a light colored crystalline product (38) containing88 or more percent dif azabicyclo-octane. This product can be further purified by retreatment with hydrocarbon as at 33 or in the manner described below.

While in the above-described operation'several fracy will not be as clean as when the described multiple distillation is followed.

While pentane isthe preferred solvent for purification of diazabicyclo-octane, other normally liquid low boiling aliphatic hydrocarbons can'be used including straight and branched chain hydrocarbons and mixtures of these, boil- 6 'The liquid effluent from the several runs was distilled in a Podbielnak column of vplate eiciency at a reflux ratio of 10/1, obtaining the following cuts:

Wt. percent of charge Initial to 130 C 11.4 ISO-143 l v 3.0 143-153? C 2.7 153-l60 C 0.8 16C-bottoms 82.1

Example II l Several separate runs were made under the same conditions as above, recycling the initial to 130 C. fraction and the 160-bottoms fraction in the ratio of 3 parts fresh diethylene triamine to 1 of recycle. Analysi-s of the liquid product from one such run, exclusive of unreacted n diethylene triamine, Visreported in Table I below.

ing in the range of up to about 130 C. Hydrocarbons boiling above about 130 C., while operable, are more difficult to separate. When using C4 compounds for this purpose, it may be necessary to adjust temperature and/or pressure to maintain the solvent in liquid state and avoid excessive losses by vaporization. The hydrocarbon liquid should preferably be employed in amounts of about 3 to 6 volumes of hydrocarbon per Volume of diazabicyclo-octane fraction of about 50% or greater diazabicyclo-octane content. Instead of the Ahydrocarbon liquid alone, the ydiazabicyclo-octane fraction at 33 may be treated first with more polar solvents such as acetone, but no particular advantagehas been found for this step.

The initial crystalline material recovered at 34`is sufliciently pure (95-|-%) for most uses of the product.

If a product of higher grade of purity is desired, this material may be further purified by sublimation (obtaining a product of 99.9l-% purity), recrystallization of the base as such, or by conversion to water-soluble salts such as the acetate or nitro-phenolates and crystallization. Alternatively, diazabicyclo-octane of high purity can be recovered directly by sublimation of the'distillate cut 30, however, the yields are considerably less than those obtained in the preferred hydrocarbon extraction procedure.

While the oily portion 37 does contain some diazabicyclo-octane, in the order of about recovery of the diazabicyclo-octane therefrom is considerably more difcult, and unless it is desired to recover certain of the other valuable products contained therein, is not believed economically feasible.

The following examples illustrate application of the described process for production and recovery of diazabicyclo-octane and piperazine as principal products.

Example l Several separate runs were made in which a charge consisting of commerical diethylene triamine was preheated to reaction temperature and passed over 4 mm. pellets of synthetic silicaalumina catalyst comprising 86% Si02 and 12% A1203 by weight, and of 34 activity index (as determined by the CAT-A method; see J. Alexander and H. G. Shimp, page R-537, National Petroleum News, August 2, 1944). The reaction con-ditions included temperature of 675 F., space rate of 1.2 Volumes of charge per volume of catalyst, at substantially atmospheric pressure. The reactor `ellluent was condensed with removal of ammonia. Liquid recovery was of the order of 90% by weight of charge, which exclusive of unreacted diethylene triamine was composed chiey of the products reported in Table I below.

- inch gauge pressure.

Example III A preheated charge consisting of 30% fresh diethylene triamine and 70% recycled products from previous operation was passed over pelleted silica-alumina catalyst of the same composition as that employed in the previous example but having an activity index (by the CAT-A method), of 46. The operating conditions were: 575 F. 0.6 volume space rate and 60 pounds per square The analysis of the liquid effluent exclusive of unreacted diethylene triamine is given in Table I. v

rThe reaction ellluent was condensed to separate ammonia, and the liquid effluent char-ged to a batch still comprising a packed column with the equivalent of 20 theoretical plates, together with collected eflluent from other runs. The collected fractions were distributed as follows:

. Wt. percent of charge Initial to C 12.9 13G-143 C 143-15'3 C 15S-160 bottoms Vol. Percent of Reactor Liquid Ehluent Example 1 Run 1 Run 2 Piperazine Alkyl Plperazines Pyrazine and Homologues'.. Diazabieyelo-octane Ethylene Diamne and Homologues 7.

The combined 13G-160 C. fractions from the above and 'other runs were collected for recovery of piperazine. The lower boiling (to 130 `C.), materials and bottoms fractions were likewise collected and the major portion utilized as recycle charge in other runs made in various ratios of recycle to fresh feed, including several runs with only recycle being charged. A minor portion of the co1- lected still bottoms was further distilled to separate out a cut boiling in the range 302 to 375 F. (circa 150- C.), and containing `approximately 45 to 50% by Of this fraction, 3928 parts by weight were charged to a Pod'bielniak column of 20 theoretical plates `at a reux ratio of 20:1, collecting a cut boiling in the range 16S-175' C. comprising about `36.4% by weight of the still charge; this cut on cooling formed a soft solid mass and contained about 60-65% diazabicyclo-'octane To 1300 parts by weight ofi this solid'mass'was added approximately 800p`arts'by weight acetone (about 1 liter acetone perl.3 kg. solid), and the mixture agitated and tlte'red'toi separate the wash liquid ALfrom undissolved solids. The solids portion was then treated twice vwith 1700 parts by weight n-pentane.

take ot acetone and pentane, leaving behind a wet solid mass, which was filtered, obtaining 412 parts by weight of dry solid analyzing 88% diazabicyclo-octane and 400 parts by weight of an oily liquid analyzing 26% diazabicyclo-octane.

Another sample of the 3D2-375 F. fraction of collected still bottoms (circa 150-190 C.), was further distilled in a column having the equivalent of 80 theoretical trays, collecting the fraction boiling over the range 17Z- 174 C.

(a) One portion vof the 172l74 C. fraction above obtained (various cuts of which analyzed respectively 76 to 89% diazabicyclo-octane), was'rerun through an 80 plate column, this time collecting the fraction boiling 17 3- 173.5 C. (analyzing 90% diazabicyclo-octane). The obtained lfraction was washed in ether and recrystallized from methyl ethyl ketone solution, then the crystals further puried by sublimation obtaining diazabicyclo-octane of 99% purity.

(b) Another portion of the l72174 C. fraction was recrystallized 3 times from acetone, obtaining diazabicyclo-octane of 99% purity.

The 99% -lpure diazabicyclo-octane obtained as above i described, melted at S-160 C. and boiled at 174-176" C. (S.T.P.). On ultimate analysis it showed the presence of the theoretical N content, and mass spectra identification showed a molal weight of 112. Titrating of the product in a 1/ l ethanol-water solution with a standard calomel electrode gives a pKZ value of 8.6 and initial pH of 10.9 in 1:1 acetone-water solution, indicating a strongly basic tertiary amine structure, which was further confirmed by Iabsence of reaction with benzene sulfonyl chloride at ordinary temperatures.

In addition to the suggested uses for diazabicyclooctane given above and those evident from its reported physical and chemical properties, it has been found that diazabicyclo-oct-ane has a strong diuretic action comparable with hexamethylene tetramine.

vThe feature of recovering diazabicyclo-octane from reaction mixtures containing the same is not limited in its applicability to reaction mixtures derived from catalytic vapor phase conversion of aliphatic amines. It will be understood that the described recovery operation can also be used in obtaining diazabicyclo-octane from reaction mixtures containing the same as a by-product of piperazine manufacture by other Vknown vapor phase as well as liquid phase conversion of such amines. The pentane purication technique finds particular advantage as applied to fractions of reaction mixtures boiling above piperazine and containing an appreciable content of difore only such limitations should be imposed as are indicated in the appended claims.

What is claimed is: l. The method of preparing diazabicyclo-(222) octane which comprises passing an alkylene polyamine having from 2 to 10 carbon atoms in vapor phase over active solid siliceous cracking catalysts at a temperature in the range of 300 to 500 C., separating fromthe re- `action product a fraction boiling above piperazine, and

recovering the'said diazabicyclo-octane from said fraction, said alkylene polyamine being one in which the aminofgroups are separatedby 2 carbon atoms;

2. The method according to claim` 1 wherein said alkylene polyamine ispethylene diamine.;

3. The method according to claim ll wherein said alkylene polyamine is diethylene triamine.` Y

4. The method according to claim 1 Wherein'said cat- `alyst comprises silica-alumina.

5. The method according to claim l wherein said catalyst is pelleted synthetic silica-alumina comprising 60 to by Weight SiO2 and 40 to 10% by Weight A1203.

6. The methodv according to claim 1 wherein said temperature lies in the range of S30-430 C.

7. The method of preparing diazabicyclo-(2 -2-2) octane which comprises passing an aliphatic amine in vapor phase over an active silica-alumina cracking catyalyst at a temperature in the range Vof 300 to 500 C., said aliphatic amine being a compound corresponding to the formula:

wherein A is a substituent selected from the group consisting of: NH2, OH

x being an integer from'l to 4, and y is selected from the group consisting of H and CH3; recovering from the reaction effluent a condensed liquid vfreed of normally gaseous products, fractionally distilling said liquid to provide at least three fractions including a first fraction boiling below piperazine, a second fraction in the approximate boiling range of piperazine, and a third fraction higher boiling than piperazine; recycling at least part of said first fraction to further contact with acidic solid siliceous catalyst,- furtherdistilling said 'third fraction and collecting therefrom a ynarrower cut fraction boiling within the range of to 190 C., triturating at least part of said narrower cut fraction including products therein boiling within the range 16S-175 C. with a normally liquid low boiling aliphatic hydrocarbon, and separating solid diazabicyclo-octane from the triturated material.

8. The method according to claim 7 wherein in the distillation of the said third fraction at least part of the bottoms boiling above 175 C. is recycled to further contact with active silicaalumina cracking catalyst. 9. The method Aaccording to claim 7 wherein materials boiling in the approximate range of pyrazine are removed from the rst fraction prior to Vsuch further contact with catalyst.

l0. The method according to claim 7 wherein said triturated narrower cut fraction from which solid diazabicyclo-octane has been separated, is further distilled to recover aliphatic hydrocarbon recycled to trituration and further quantities of solid diazabicyclo-octane are recovered from the residue of said last-mentioned distilla- Vtion.

1l'. The method of .preparing diazabicyclo-(2-22) octane which comprises contacting an aliphatic amine charge comprising diethylene triamine with acidic silicaalumina catalyst at a temperature in the range of 330 to 430 C., condensing the reaction effluent to remove normally gaseous products therefrom, distilling the liquid condensate to obtain at least three fractions therefrom including: a first fraction boiling up to about 12S-130 C., a second fraction boiling above said rst fraction and up to about 150-160 C., and third fraction comprising distillation residue boiling above said second fraction; distilling said third fraction to separate therefrom a cut boiling within the rangeY of about 150 to 190 C., separatingV from atleast part of said cut a fraction boiling 9 10 roughly in the range of diazabicyc1o(2-22)octane, and References Cited in the ile of this patent recovering solid diazabicyclo-octane from said lastnamed fraction by treatment thereof with a liquid ali- A UNITED STATES PATENTS phatic hydrocarbon boiling up to about 130 C. 2,454,404 P-fann et al. Nov. 23, 1948 12. The method according to claim 11 wherein said 5 2,467,205 Gresham et al. Apr. 12, 1949 aliphatic hydrocarbon is n-pentane.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIDN May 17v 1960 Patent No., 2,937,176

'Elbert C., Herrick It is hereby certified that error appears in the printed specification of the' above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column L line 50g for "thiamine" read triarnine column Y line 2, for "Podbielnak" read Podblelnlak --73 line 27, for "5750 F," read 575 F.

Signed and sealed this 4th day of April l9l (SEAL) Attest: ERNEST W. SWIDER MXXXNK ARTHUR W. cRocKER Attesting Ofcer Acting Commissioner of Patents 

1. THE METHOD OF PREPARING DIAZABICYCLO-(2.2.2)OCTANE WHICH COMPRISES PASSING AN ALKYLENE POLYAMINE HAVING FROM 2 TO 10 CARBON ATOMS IN VAPOR PHASE OVER ACTIVE SOLID SILICEOUS CRACKING CATALYSTS AT A TEMPERATURE IN THE RANGE OF 300 TO 500*C., SEPARATING FROM THE REACTION PRODUCT A FRACTION BOILING ABOVE PIPERAZINE, AND RECOVERING THE SAID DIAZABICYCLO-OCTANE FROM SAID FRACTION, SAID ALKYLENE POLYAMINE BEING ONE IN WHICH THE AMINO GROUPS ARE SEPARATED BY 2 CARBON ATOMS. 